Extracts and constituents of Edelweiss (Leontopodium alpinum) enhance cholinergic transmission: AChE inhibitory, ACh-increasing and memory improving properties

Extracts of the roots of Edelweiss (Leontopodium alpinum Cass.) were activity guided fractionated for their acetylcholinesterase (AChE) inhibitory activity in an in vitro enzyme test and in a TLC assay with bioactivity staining, both based on Ellman's method [1]. Since results of the applied methods were contradictory the ability of the crude extract and its sub-fractions to enhance acetylcholine (ACh) in rat brain was studied using the push-pull technique.

The sub-fraction with the highest in vivo activity consisted of a mixture of four sesquiterpenes: modhephene, silphinene, isocomene and β-isocomene. The in vivo-efficacy of the single compounds did not correlate with the in vitro AChE inhibitory potency and is obliviously mediated by another mechanism of action. The most potent sesquiterpene, isocomene, was further investigated with behavioural tasks in mice for cognition-improving and cholinergic transmission-enhancing properties. The compound (42 nM; i.c.v.) improved the object recognition in scopolamine-impaired mice (50 nM; i.c.v.) and showed nootropic-like effects in the T-maze alternation task in normal and scopolamine-treated mice (50 nM; i.c.v.). Additionally, the sesquiterpene (42 nM; i.c.v.) reduced locomotor activity of untreated mice in the open field task while the activity induced by scopolamine (50 nM; i.c.v.) was abolished. The effects of isocomene in vivo including the amelioration of cholinergic deficit in the behavioural tasks are in accordance with those of cholinergic transmission-enhancing substances [2]. The mechanism of action seems not to be caused by AChE inhibition and remains to be elucidated. Taken together, isocomene and related constituents of Leontopodium deserve further interest because of the significant anti-amnesic and cholinergic transmission-related effects of yet unidentified mechanism of action.

Acknowledgements: This work was supported by the Austrian Science Fund (P18379-B11).

References: [1] Ellman, GL., et al. (1961) Biochem Pharmac. 7: 88–95. [2] Prast, H., Rollinger J., Schwaiger S., Stuppner H. (2007) PCT Int. Appl. A1 20070118.